ES2428167T3 - Anti-MRSA active bactericidal pharmaceutical composition containing carbapenemos - Google Patents

Abstract

Active pharmaceutical composition for Staph. Aureus resistant to methicillin anti-MRSA and bactericide containing a carbapenem antibiotic and epicillin, their salts, prodrug ester or amidic derivatives of prodrug.

Description

Anti-MRSA active bactericidal pharmaceutical composition containing carbapenems Description and background of the invention [0001] This invention relates to 2-S / O-and S / N acetal derivatives of carbapenem-3 acid formaldehyde

carboxylics of general formula I

where R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes a pharmaceutically acceptable group that is linked to the remaining part of the molecule by a carbon-oxygen single bond or a carbon-nitrogen single bond and which selected from the group comprising as substituted or unsubstituted: alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, N-heterocyclyl, heterocyclyloxy, heterocyclylcarbonyloxy, heterocicliltiocarboniloxi, acyloxy, tioaciloxi, alkoxycarbonyloxy, carbamoyloxy, thiocarbamoyloxy, heterocicliloxicarboniloxi, heterocicliloxitiocarboniloxi, N-heterociclicarbamoiloxi, N- heterocicliltiocarbamoiloxi, heterocyclylcarbonylamino, heterocicliltiocarbonilamino, heterocidiloxicarbonilamino, acylamino, alkoxycarbonylamino, alkoxythiocarbonylamino, tioaciclamino, Nheterociclilcarbamoilamino, N-heterocicliltiocarbamoilamino, carbamoylamino, tiocarbamoilamino, imidoilamino, guanidino, N-heterocyclyl-alkoxycarbonylamino, N-heterocyclyl-a alkylthiocarbonylamino and N-sulfonylamino where the above-mentioned parts of the molecule alkyl, alkenyl, alkynyl, acyl, thioacyl or imidoyl contain from 1 to 6 carbon atoms and the heterocyclyl group is monocyclic or bicyclic and contains from 3 to 10 ring atoms , of which one or more are selected from the series comprising: oxygen, sulfur and nitrogen and where the substituents of the groups mentioned above R may be: alkyl, acyl, thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy , amidinoalcoxi, guanidinoalcoxi, acyloxy, heterocyclyloxy, alquilheterocicliloxi, hidroxialquilheterocicliloxi, aminoalquilheterocicliloxi, carbamoyl, alquilocarbamoil, dialquilocarbamoil, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy, thiocarbamoyl, alquiltiocarbamoil, dialquiltiocarbamoil, thiocarbamoyloxy, alquiltiocarbamoiloxi, dialquiltiocarbamoiloxi, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalquilamin oalquiltio, dialquilaminoalquiltio, amidinoalquiltio, acylthio, heterocyclylthio, alquilheterocicliltio, hidroxialquilheterocicliltio, aminoalquilheterocicliltio, carbamoiltio, monoalquilcarbamoiltio, dialquilcarbamoiltio, tiocarbamoiltio, alquiltiocarbamoiltio, dialquilcarbamoiltio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoilamino, alquilimidoilamino, dialquilimidoilamino , tetraalkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alquilheterociclilcarbonilamino, acylamino, amidino, monoalquilamidino, dialquilamidino, guanidino, alkylguanidino, -dialkylguanidino, carbamoylamino, tiocarbamoilamino, alquilcarbamoilamino, tiocarbamoilamino, alquiltiocarbamoilamino, nitro, chlorine, Bromine, fluoro, iodo, cyano azido, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfamoyloxy, alkylsulfamoyloxy, alkylsulfonyloxy or sulfo, sulfoxy, carboxamido, N-monoalkylcarboxamido, N, N-dia alkylcarboxamido or carboxy, where the substituents, independently of each other, meet once

or several times and its alkyl group contains between 1 and 6 carbon atoms, and where the heterocyclic fraction is monocyclic or bicyclic and contains between 3 and 10 ring atoms, from which one or more are selected from the series comprising: oxygen , sulfur and nitrogen, these compounds and their pharmaceutically acceptable salts, esters and amide derivatives are useful as antibiotics and as β-lactamase inhibitors.

[0002] R3 pharmaceutically acceptable groups, which are connected through a single carbon-oxygen bond or a simple carbon-nitrogen bond are common groups, for example, in the field of β-lactam antibiotics or inhibitors of β-lactamase. Such groups are found, for example, in M.S. Sassiver, A. Lewis in "Advances in Applied Microbiology", Ed. D. Perlman, Academic Press N.Y. (1970) or in many patents, e. g. US Pat. 5,096,899.

[0003] The term "acceptable pharmaceutical salt" as used in this case and in the claims includes non-toxic salts of acids and bases and salts of zwitterionic species. Salts with a base include inorganic salts such as sodium, potassium, magnesium and calcium, or ammonium and salts with non-toxic amines such as trialkylamines, alkanolamines, arginine or cyclic amines such as piperazine, procaine and other amines, which have been used to form salts of carboxylic acids. Salts with an acid include salts of inorganic acids such as hydrochloride, sulfate, phosphate and the like and salts of organic acids such as acetate, maleate, citrate, succinate, ascorbate, lactate, fumarate, tartrate and oxalate and other organic salts with acids that have been used to form salts with amines.

[0004] Pharmaceutically acceptable esters and amide derivatives as used herein serve as prodrugs when hydrolyzed in the body to produce the antibiotic per se. They are preferably administered orally since hydrolysis occurs mainly under the influence of digestive enzymes. Parenteral administration can be used in some cases where hydrolysis occurs in the blood. Examples of esters

Pharmaceutically acceptable and amide derivatives include physiologically hydrolysable esters and amides known and used in the field of penicillin and cephalosporin as, e. g. in Advances in Drug Res 17,197 (1988). Such esters and amide derivatives are prepared by conventional techniques known in the art.

[0005] The compounds used in the invention have different asymmetric centers and can thus exist in different stereochemical forms. The invention includes the mixture of isomers and individual stereoisomers. The most preferred compounds of formula I have 1 R, 5S and 6S configuration of the carbapenem substituted nucleus and 1'R or 1'S configuration of the 6- (1-hydroxyethyl) side chain. Additionally, asymmetric carbon atoms can be included in the R3 substituent. The invention includes compounds with R and S configuration in substituent R3.

[0006] On the other hand, the invention also relates to conventional carbapenem antibiotics, which are commercially available or are investigated for clinical use. A full report on such carbapenem antibiotics is given in Heterocycles 54, 497, 2001.

[0007] This invention also relates to pharmaceutical compositions containing carbapenem antibiotics in combination with epicillin and its preparation. It also refers to treatment methods where such compositions are used when an antibiotic effect is indicated.

[0008] The terminology for compounds of this class may be based on the name of carbapenem root "which employs a simple and trivial nomenclature system (used in the general description). Alternatively, these compounds may also be described by the chemical nomenclature. Abstract System (bicycles nomenclature), which is more appropriate to describe individual compounds of this family, therefore the Chemical nomenclature

[0009] β-lactam antibiotics, such as penicillins or cephalosporins, have been partially ineffective in the therapy of infectious diseases due to bacterial resistance. In addition to the natural resistance of certain bacteria, many strains of pathogenic microorganisms have acquired resistance with the continued use of large-scale antibiotics. Thus, many species of Staphylococcus aureus have become resistant against penicillins and many Gram-negative bacteria such as Enterobacter cloacae, Pseudomonas aeruginosa or even Escherichia coli have acquired resistance against cephalosporins.

[0010] Although the carbapenenes according to the invention are very active as mono-substances against Staphs. aureus sensitive to penicillin and those resistant to penicillin Staph. aureus that produce β-lactamase, are not active against Staph. methicillin-resistant aureus (MRSA) or Staph. methicillin resistant epidermis (MRSE). For example, four representative carbapenemos showed only low activity against Staph. Innsbruck (methicillin resistant) with small zones of 0-12 mm inhibition in the plaque test as described in US Pat. 6,482,818 or EP 1 100 800. The lack of activity against MRSA in the category of carbapenems is also documented, p. eg in EP 384 410. MRSA resistance levels have increased considerably in the last decade and already in 2000 all marketed carbapemos completely lacked anti-MRSA activity (Journal of Antimicrobial Chemotherapy 2000, 45,379). Consequently, current research in the field of antibiotics focuses on methods to overcome the increasing resistance of MRSA and MRSE, which may become a major threat to human life in the near future.

[0011] Staphylococcus aureus is one of the most abundant bacterial pathogens in infectious diseases. In 2004, of the diseases caused by Staph. aureus, 22. 6% were declared resistant to methicillin or oxacillin (PEG-Resistenzstudie, Pablo Ehrlich Gesellschaft für Chemoterapie e.V, www.p-e-g.org). Eradication of MRSA and MRSE is particularly difficult, because many species of these bacteria are also resistant to non-β-lactam antibiotics, for example quinolone antibiotics.

[0012] MRSA resistance is not due to the formation of ß-lactamase but to a completely different mechanism, namely a lack of, or an inadequate binding of the antibiotic to a PBP 2a penicillin binding protein, present in all MRSA strains. From this point of view, pharmaceutical products of penicillins or cephalosporins with β-lactamase inhibitors are not a solution to overcome MRSA resistance and the combination of amoxicillin and clavulanate is also inappropriate in infections due to MRSA. (Journ. Antimicrob. Ter. 1989,49.).

[0013] DATABASE MEDLINE, US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US, abstract of SAIONJI K ET AL: The Japanese Journal of Antibiotics, 43 (10) .1685-1697 (1990), Database accession no. NLM2086811, discloses a combination of imipenem-ampicillin against MRSA;

[0014] EP 0 041 768 A, discloses a bactericidal association of alkylidenepenem / penicillin.

[0015] Another method attempted to overcome methicillin resistance was published in EP 384 410 with the description of a synergism between three carbapenenes and penicillins or cephalosporins. The use of piperacillin and cefotiam in combination with imipenem was considered especially preferable in EP 384410. However, the above-mentioned combinations described by the prior art are hardly sufficiently effective with published average MICs of 27.9 μg / ml for piperacillin / imipenem or 14.4 μg / ml for cefotiam / imipenem. A synergism between meropenem and cefpiramide (Eur. J. Clin. Microbiol. Infect. Dis. 10.77-84.1991) was also provided with average MICs of 13.2 μg / ml. Such high levels are impossible or very difficult to maintain in vivo during the entire therapy. Although these combinations of the prior art were more active than the individual components alone, a substantial improvement was desirable.

[0016] The fact that in EP 384410 it was not validated in Germany, in the US and in other countries in 1995, indicates that the combinations described by the state of the art lack practicability.

[0017] As all commonly used commercially available carbapenems are administered parenterally because they do not have sufficient oral activity (Infection 14; (1986), suppl. 2, S 115) an orally active composition with a penicillin or a cephalosporin (orally active) and a carbapenem could not be prepared through the state of the art. An active oral composition is desirable for the so-called "sequential therapy" in which treatment begins with a parenteral formulation in the hospital and continues with oral therapy after an earlier discharge from the patient. A more recent overview of oral carbapenemos was given in Curr. Med. Chem. -Antiinfective Agents, 2000, 1, 1.

[0018] The antibiotic currently chosen against infectious diseases of MRSA is linezolide, a bacteriostatic agent (Chemotherapie Journal. 2002, 11, 113-6 2002, 11,113-6).

[0019] To overcome MRSA resistance, we investigated the compositions of 29 conventional traditional β-lactam antibiotics with 15 carbapenenes for possible synergism. For these investigations two highly resistant MRSA hospital strains were used, ie Staph. Innsbruck and MRSA 7268/02. Staph. Innsbruck is resistant to oxacillin, methicillin, ampicillin and ciprofloxacin, MRSA 7268/02 is multi-resistant to oxacillin, methicillin, enrofloxacin, clindamycin, ciprofloxacin and moxifloxacin. Such highly resistant bacteria have appeared recently and were not frequent 10 years ago.

[0020] Surprisingly we found that of the conventional β-lactam antibiotics investigated (12 penicillins and 17 cephalosporins) epicillin showed an outstanding effect against high-resistance MRSA when combined with carbapenenes. The synergistic effect of epicillin / imipenem was much greater than that of piperacillin / imipenem or that of cefotiam / imipenem used in the state of the art. The count of colony forming units (cfu) as a function of time revealed that epicillin / imipenem at 2 + 2 μg / ml was also much faster eradicating MRSA 7268/02 than other penicillin / imipenem or cephalosporin / imipenem preparations described by the state of the art, including that of ampicillin / imipenem. With the epicillin / imipenem combination the cfu number decreased by 99.6% after 6 hrs of incubation at 37 ° C, revealing that this preparation is strongly bactericidal against MRSA 7268/02. In contrast, the especially preferred combinations described by the prior art, specifically piperacillinfimipenem or cefotiam / imipenem were only marginally bactericidal with reductions of cfu in 17 or 71% respectively (table 1) [0021] Neither epicillin nor linezolide showed No significant reduction of cfu, when used alone. Meropenem at 4 μg / ml was also less bactericidal than the epicillin / meropenem composition at 2 + 2 μg / ml (Table 2)

[0022] Using the same bacteria and concentrations, the epicillin / meropenem combination shows a reduction of cfu by 99.7% compared to 42.5% for piperacillin / meropenem. Similarly, with Staph. aureus Innsbruck at 4 + 4 μg / ml, the reduction of cfu after 6 hrs of incubation at 37 ° C with epicillin / meropenem was 100% compared to a marginal 10% reduction achieved with piperacillin / meropenem (table 3) . The

The bactericidal activity of epicillin / meropenem was also superior to ampicillin / meropenem and amoxicillin / meropenem. Similarly, other epicillin / carbapenem combinations also have a very rapid bactericidal action.

[0023] In short, the combination of epicillin with a carbapenem is more active, faster and more bactericidal than the corresponding preparations in the state of the art eradicating MRSA.

[0024] The high high bactericity of this combination is in sharp contrast to the current antibiotics used against MRSA, ie linezolide and vancomycin, both having only bacteriostatic activity (Chemotherapie Journal. 2002, 11,113-6; Antimicrob. Ag. Chemoter. ( 2005), 49,2735).

[0025] The high synergistic activity of the epicillin / meropenem combination is also observed in the plaque test with the following diameters of inhibition zones:

MRSA 7268/02 Staph. Innsbruck

Epicillin (only) 30 μg 14 mm 10 mm Meropenem (only) 10 μg 13 mm 14 mm Epi and Mero 30 + 10 μg 23 mm 20 mm Vancomycin 30 μg 19 mm 20 mm

[0026] Unlike the zones of inhibition caused by the individual substances epicillin or meropenem, and a

Unlike all the individual β-lactams investigated, those generated by the combination of epicillin and meropenem remain transparent after an additional incubation (40 hr) at 37 ° C, confirming the strong bactericidal effect mentioned above. This effect is also observable with other epicillin / carbapenem combinations. Therefore the use of an epicillin composition and a carbapenem is strongly preferred.

[0027] The high bactericity of this combination is also in sharp contrast with that of, for example, oxacillin / meropenem. No synergism of the last composition was observed in the plaque test.

MRSA 7268/02 Staph. Innsbruck

Oxacillin (only) 30 μg 0 mm 0 mm Meropenem (only) 10 μg 13 mm 13 mm Oxacillin and Mero 30 + 10 μg 13 mm 13 mm

[0028] The rapid and high bactericidal activity of a combination of two β-lactam compounds, for example epicillin and Meropenem against MRSA is surprising. It has been stated by prior art that all ßlactam compounds should be declared "resistant" to methicillin (or oxacillin) (W. Cullmann in "Antibiotics and Chemotherapy" Vol. 47 (Oral Cephalosporins), p. 79 (1995 This quotation constitutes a prejudice in the state of the art against the present invention.

[0029] The use of carbapenemos and epicillin to eradicate MRSA or MRSE is not known in the prior art. There was no reference available in Sci-Finder Scholar (Am.Chem.Society) using both keywords "epicillin and mrsa", while 9082 references appeared with the (single) keyword "mrsa".

[0030] An object of the present invention is to provide a novel pharmaceutical composition of an antibiotic of carbapenem and epicillin that proves to have a very broad antibacterial spectrum including MRSA and MRSE. The aforementioned synergism with epicillin is also inherent in oral active carbapenems.

[0031] Epicillin was widely used in the 1970s and 1980s as an active antibiotic orally and parenterally. 40 A clinical experience report is given p. ex. in N. Z. med. J. 75.77 (1972). Carbapenemos are either commercial products or are prepared by a method described in EP 1 100 800 or are described elsewhere, e.g. eg in Heterocycles, 54, 497 (2001); Drugs 61, 553 (2001); Current Opinion in Anti-Infective Investigational Drugs 2, 133 (2000);

[0032] As mentioned above, the selection of carbapenenes in the preparation of synergistic mixtures is not very critical. In fact the 18 carbapenemos investigated so far showed a pronounced synergism against MRSA when combined with epicillin. On the other hand, the selection of partner antibiotics is more crucial. Unlike prior art teaching, only epicillin can provide sufficient bactericidal activity to eradicate MRSA that has a high level of resistance in synergistic action with carbapenems.

[0033] For oral use, prodrug esters or prodrug amides derived from epicillin can also be applied to prepare synergistic preparations. Such prodrugs are known in the art and are described e. g. in Advances in Drug Res. 17,197 (1988) or in Curr. Med. Chem. -Anti-Infective Agents 2002, 1,1. Examples of such prodrug esters derived from similar antibiotics are pivampicillin, bacampicillin and pivcefalexin. An example of amide derivatives of prodrug is hetacillin.

[0034] Examples of conventional carbapenemos useful in the preparation of synergistic mixtures are the carbapenemos described in EP 1 100 800, imipenem, imipenem / cilastatin, meropenem, panipenem, panipenem / betamipron, ertapenem, biapenem, doripenem, saftrinem, lenapenem, lenapenem, lenapenem tomopenem S-4661, SM 216601, GV 129606; ZD-4433; ER-35786; R-83201, R 95867; DU-6681; BO-2502A, BO-3482; DK-35C, DA-1131, S4661; L-646591; L-786,392; L-695,256; L-786,392; L-084; L-036; GV104326; GV-118819, GV 143253; MK-0826, J- 110,441; J-111225; FR-21818; DX-8739; CS-023; ME-1036, CP 5068; OCA-983, CL 188624; CL-190294; T-5575, PZ-

601

[0035] Equivalently, for oral use, hydrolysable prodrug esters, also known in the field of carbapenems (Antimicrob. Agents, Chemother. 1998, 42,1527; Heterocycles 54,497 (2001), Curr. Med. Chem. - Antiinfective Agents 2002, 1,1), can be used to prepare synergistic mixtures. Examples of carbapenemos prodrugs are CS-834; L-084; GV118819, DZ- 2640; CL191121.

[0036] The proportion of carbapenem to epiciilin may vary within a wide range. Useful ratios are 1: 10 a

10: 1. Preferred ratios are 1: 4 to 4: 1. Strongly preferred ratios are 1: 1 to 1: 3

[0037] The aforementioned combination of epicillin and a carbapenem can be supplemented with a variety of other biologically active ingredients. Examples are dehydropeptidase inhibitors such as betamipron or cilastatin, which are commonly used to protect carbapenenes such as imipenem.

[0038] The progressive and rapid reduction of colony forming units makes inventive combinations the method chosen as the initial therapy for suspected or confirmed MRSA and MRSE infections.

[0039] A major drawback with infectious diseases is the appearance of life-threatening sepsis, a severe disease caused by an infection of the blood flow. It is estimated that bacterial sepsis kills more than 200,000 people per year in the US (www.nursing-home-abuse-resource.com). Sepsis is also common with MRSA. To avoid such a threat, bacterial units can be reduced by the initial bactericidal therapy according to the invention. Then a secondary therapy with an antibiotic, for example an antibiotic other than β-lactam, can continue to eradicate the number of bacteria greatly diminished. Therefore, the inventive combination can also be supplemented with antibiotics. Examples for this type of supplements are sulfonamides, for example sulfathiazol / trimethoprim, tetracycline, for example aureomycin or doxycycline, aminoglycosides, for example clindamycin, glycopeptides, for example teicoplanin, vancomycin, quinolones, for example ciprofloxacin, moxifloxacin, for example, gatifloxacin, for example rifampicin, macrolides, for example erythromycin or other bacteriostatic agents, for example linezolid.

[0040] A selection of pharmaceutical products according to the invention also showed high antibacterial activity against bacteria other than staphylococci: in the disk susceptibility test, the simultaneous application of 30 micrograms of epicillin and 10 micrograms of carbapenem gave the following inhibition diameters : E. coli (27-40 mm), E. cloacae (23-27 mm), Mr. pneumoniae (31-44 mm), Enterococcus faecalis (21-40 mm) and Ps. aeruginosa (13 - 26 mm). These data correspond to those of a clinically useful injectable carbapenem used as the sole substance as described in Journ. Antimicrob Chemotherapy 24; (1989), Suppl. A, 253.

[0041] The new pharmaceutical products are valuable bactericides for use in human and veterinary medicine. Due to their large antibacterial spectrum they can also be used as medicines to treat confirmed or suspected infections caused by bacteria other than the gram-positive and gram-negative ones mentioned above, that is to say by MRSA, MRSE, Moraxella it catarrhalis, Haemophilus influenzae, pneumoniae Klebsiella Bacillus subtilis, Salmonella tifosa, Enterobacter cloacae, Citrobacter, pseudomonas aeruginosa, Proteus bacteria and anaerobic bacteria.

[0042] A great field of antimicrobial therapy using carbapenemos as unique substances is sinusitis, an inflammation of the respiratory tract. Bacterial sinusitis is caused predominantly by streptococcus pneumomiae, moraxella it catarrhalis, haemophilus influenzae, some anaerobic and penicillin-sensitive bacteria (producing ß-lactamase) Staphylococcus aureus and MRSA (often appear in mixed infections Journal of laryngology and otology (2005); 119 (4), 251). Carbapenemos alone can effectively eradicate all these bacteria except MRSA. The combination of a carbapenem / epicillin composition fills the void that arises from MRSA resistance. Therefore, the inventive combination is especially useful for curing bacterial sinusitis. In addition, other infectious diseases, for example urinary tract infections or lesions, confirmed or suspected of being caused by MRSA or MRSE, can be cured by application of the pharmaceutical composition according to the invention.

[0043] The new active bactericidal pharmaceutical compositions for MRSA according to the invention are valuable remedies that are active against most gram-negative and gram-positive pathogens including also penicillin and cephalosporin-resistant bacteria and anaerobic bacteria. Because of their very broad antibacterial spectrum, they are valuable medications to use, for example in intensive care units. On the other hand, since epicillin is an active oral drug, its combination with oral active carbapenems also provides valuable remedies for the rapid oral treatment of community-acquired infections.

[0044] The pharmaceutical compositions according to the invention may contain the free acid and in particular the alkaline and earth metal salts or the zwitterionic species of their components. They are useful bactericides and can be used to eliminate pathogens from medical and dental equipment for the elimination of microorganisms and for therapeutic use in humans and animals. For the latter purposes, pharmaceutically acceptable salts or their active components can be used, as they are known per se and used in the administration of penicillins and cephalosporins. These salts can be used together with pharmaceutically acceptable liquid and solid excipients to form suitable dosage unit forms such as pills, tablets, capsules, suppositories, syrups, elixirs and the like, which can be prepared by processes that are known per se.

[0045] The new pharmaceutical products can also be used as feed additives for animals, to preserve food or feed products and as disinfectants. For example, they can be used in aqueous preparations in concentrations ranging from 0.1 to 100 parts of antibiotic / million parts of solution for the destruction and inhibition of the growth of harmful bacteria in medical equipment and as bactericides in industrial applications, for example in Water-based and soft water paints for paper mills, for the inhibition of the growth of harmful bacteria.

[0046] The new pharmaceutical composition according to the invention can be used alone or together with other active components in any of a large number of pharmaceutical products. These preparations can be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They can be administered orally, intraperitoneally, intravenously or intramuscularly.

[0047] The preparation is preferably administered in a form that is convenient for absorption through the gastrointestinal tract. Tablets and capsules for oral administration may be in unit dosage form and may contain usual medicament excipients, such as binders, for example syrup, gum arabic, gelatin, sorbitol or polyvinylpyrrolidone, fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, lubricants, for example magnesium stearate, talc, polyethylene glycol or silica, disintegrants for example potato starch, or acceptable humidifying agents such as sodium lauryl sulfate. The tablets can be coated by processes that are known per se. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs and the like or may exist as dry products, for example for reconstitution before using water or other suitable excipients. Liquid preparations of this type may contain additives that are known per se, such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, or edible oils hydrogenated, for example almond oil, fractionated coconut oil, oil esters, propylene glycol or ethyl alcohol, preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories contain suppository bases that are known per se, for example cocoa butter or other glycerides.

[0048] Preparations for injection may be in the form of a dose unit in ampoules or in containers containing different doses with an added preservative. The preparations may be in the form of suspensions, solutions or emulsions in aqueous or oleaginous excipients, and may contain formulating agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the active component may be powdered for reconstitution before using a suitable excipient, for example, sterile pyrogen-free water.

[0049] The preparations may also be in a form suitable for absorption through the mucous membranes of the nose and neck or bronchial tissue, and may be in the form of powders or sprays or liquid inhalants, sweet to suck, as solutions colored throat fluids, etc. For eyes and ear medications, the preparations can be used as an individual capsule in liquid or semi-solid form or it can be

5 use as drops, etc. Topical applications may exist or may be formulated in hydrophobic vehicles such as ointments, creams, lotions, tinctures, powders, etc.

[0050] The two active components, ie carbapenem and epicillin can also be administered separately. For example, a carbapenem can be administered intravenously and epicillin orally. Conveniently not

However, the two active agents will be administered by the same route, for example, intravenously or orally.

[0051] The composition according to the invention may contain, in addition to the excipient, other components such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity control agents or flavorings or the like.

[0052] The composition according to the invention may also contain, in addition to the excipient, enzymatic inhibitors, for example betamipron or cilastatin (Merck Index, 11 th ed. 2275) to increase the therapeutic effect.

[0053] For veterinary medicine, the composition may be formulated, for example, as an intra-breast preparation

20 in vehicles of long duration or quick release. The dose to be administered is highly dependent on the condition of the subject to be treated and the weight of the host, and on the method and frequency of administration. In general, a daily oral dose contains approximately 10 to 200 mg of active component / kg of body weight of the subject in case of one or more administrations per day. A preferred daily dose for adult humans is in the range of 20 to 120 mg of active component / kg of body weight.

[0054] The preparation according to the invention can be administered in various dosage unit forms, for example in solid or liquid dose forms that can be taken orally. The preparation may contain 0.1 to 99% of active material per unit dose, either in solid or in liquid form. The preferred range is approximately 10 to 60%. The preparations generally contain 15 to about 1500 mg of active component but it is

30 it is generally preferable to use a dose amount in the range of 250 to 1000 mg. In the case of parenteral administration, the unit dose is normally the pure compound in a solution of sterilized water or in the form of a soluble powder, which can be dissolved.

[0055] The examples below illustrate the antibacterial activities, as compared to pharmaceutical compositions described in the prior art. In addition, preparations and methods of treatment according to the invention are exemplified.

Example 1 40

Antibacterial activity determined by the agar diffusion method

[0056] Inhibition zone diameters were determined on Difco nutritive agar (10 ml) in sterile dishes (8.5

45 cm) using approx. 106-107 colony forming units. 0.2 ml of a bacterial suspension (overnight culture in Difco nutrient broth) was mixed at 52 ° C with the sterile liquid agar. It solidifies at room temperature. Sterile filter discs (6mm) were placed on the agar surface. Appropriate volumes of 0.2% aqueous antibiotic solutions were transferred to the discs with a precision syringe. Alternatively, commercial impregnated discs (Oxoid) were used.

[0057] The diameter of the zone of inhibition was measured after 20 hrs at 37 ° C. For the determination of bactericidal activity, incubation at 37 ° C was continued for an additional 40 hrs. A clear zone of inhibition after further incubation indicated bactericity (B).

55 MRSA strain test 7268/02

[0058]

Epicillin (30 μg) Meropenem (10 μg) Epicillin + meropenem (30 + 10 μg) 14 13 23 (B)

Epicillin (30 μg) Imipenem (10 μg) Epicillin + imipenem (30 + 10 μg) 14 14 24 (B)

Epicillin (30 μg) R 83201 (10 μg) Epicillin + R 83201 (30 + 10 μg) 12 9 20 (B)

Epicillin (30 μg) Ertapenem (10 μg) Epicillin + ertapenem (30 + 10 μg) 12 0 16 (B)

Epicillin (30 μg)

GH 478 (10 μg) Epicillin + GH 478 (30 + 10 μg)

14

 0 23 (B)

Epicillin (30 μg)

GH 570 (10 μg) Epicillin + GH 570 (30 + 10 μg)

12

 0 19 (B)

Epicillin (30 μg)

GH 519 (10 μg) Epicillin + GH 519 (30 + 10 μg)

12

 0 16 (B)

Cefaclor (30 μg)

GH 478 (10 μg) Cefaclor + GH 478 (30 + 10 μg)

eleven

 0 19

Amoxicillin (30 μg)

GH 478 (10 μg) Amoxicillin + GH 478 (30 + 10 μg)

0

0

17

Amoxiclav (30 μg)

GH 478 (10 μg) Amoxiclav + GH 478 (30 + 10 μg)

13

 0 17

Ampicillin (30 μg)

GH 478 (10 μg) Ampicillin + GH 478 (30 + 10 μg)

12

 0 twenty-one

Cloxacillin (30 μg)

GH 478 (10 μg) Cloxacillin + GH 478 (30 + 10 μg)

0

0

0

Dicloxacillin (30 μg)

GH 478 (10 μg) Dicloxacillin + GH 478 (30 + 10 μg)

0

0

0

Cefazolin (30 μg)

GH 478 (10 μg) Cefazolin + GH 478 (30 + 10 μg)

0

0

eleven

Cefalotin (30 μg)

GH 478 (10 μg) Cefalotin + GH 478 (30 + 10

0

0

9

Cefoxitin (30 μg)

GH 478 (10 μg) Cefoxitin + GH 478 (30 + 10 μg)

0

0

0

Cefuroxim (30 μg)

GH 478 (10 μg) Cefuroxim + GH 478 (30 + 10 μg)

0

0

14

Cefdinir (30 μg)

GH 478 (10 μg) Cefdinir + GH 478 (30 + 10 μg)

0

0

0

Cefotaxime (30 μg)

GH 478 (10 μg) Cefotaxime + GH 478 (30 + 10 μg)

0

0

10

Oxacillin (30 μg)

GH 478 (10 μg) Oxacillin + GH 478 (30 + 10 μg)

0

0

0

Ceftriaxon (30 μg)

GH 478 (10 μg) Ceftriaxon + GH 478 (30 + 10 μg)

 (keep going)

0

0

10

Carbenicillin (30 μg)

GH 478 (10 μg) Carbenicillin + GH 478 (30 + 10

0

10 fifteen

Cefazolin (30 μg)

GH 478 (10 μg) Cefazolin + GH 478 (30 + 10 μg)

0

0

13

Cefoperazone (30 μg)

GH 478 (10 μg) Cefoperazone + GH 478 (30 + 10

9

0 10

Cefotiam (30 μg)

GH 478 (10 μg) Cefotiam + GH 478 (30 + 10 μg)

10

 0 14

Cefotiam (30 μg)

Imipenem (10 μg) Cefotiam + imipenem (30 + 10 μg)

0

8 12

Piperacillin (30 μg)

Imipenem (10 μg) Piperacillin + imipenem (30 + 10

0

8 13

Cefsudolin (30 μg) 0

GH 478 (10 μg) 0 Cefsudolin + GH 478 (30 + 10 μg) 0

5

Vancomycin (30 μg) 19

GH 478: (1R.5S.6S) -6 - [(R) -1-hydroxyethyl] -2-methoxymethylthio-1-methylcarbapen-2-em-3-potassium carboxylate GH 570: acid (1R.5S.6S ) -2 - [(2-Aminoethyl) oxy] methylthio-6 - [(R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic 10 GH 519: (1R.5S.6S) -2 - [(N-acetylamino) methylthio] -6 - [(R) -1-hydroxyethyl] -1-methyl-carbapenen-2-em-3- potassium carboxylate Test strain: Staph. Innsbruck Diameter of the zone of inhibition (mm) Epicillin (30 μg) Meropenem (10μg) Epicillin + Meropenem (30 + 10μg) 10 14 20 (B) Epicillin (30 μg) Imipenem (10 μg) Epicillin + imipenem (30 + 10 μg) 10 14 22 (B) Epicillin (30 μg) GH478 (10 μg) Epicillin + GH 478 (30 + 10 μg) 14 0 19 (B) Epicillin (30 μg) R 83201 (10 μg) Epicillin + R 83201 ( 30 + 10 μg) 12 11 20 (B) Epicillin (30 μg) Ertapenem (10 μg) Epicillin + ertapenem (30 + 10 μg) 12 0 16 (B) Epicillin (30 μg) GH 570 (10 μg) Epicillin + GH 570 (30 + 10 μg) 12 0 17 (B) Epicillin (30 μg) GH 519 (10 μg) Epicillin + GH 519 (30 + 10 μg) 12 0 16 (B) Amoxicillin (30 μg) GH 478 (10 μg ) Amoxicillin + GH 478 (30 + 10 μg) 10 0 17 Amoxiclav (30 μg) GH 478 (10 μg) Amoxiclav + GH 478 (30 + 10 μg) 13 0 17 (continued) Test strain: Staf. Innsbruck Inhibition zone diameter (mm) Ampicillin (30 μg) GH 478 (10 μg) Ampicillin + GH 478 (30 + 10 μg) 12 0 17 Penicillin G (30 μg) GH 478 (10 μg) Penicillin G + GH 478 (30 + 10 μg) 12 0 14 Cefixim (30 μg) GH 478 (10 μg) Cefixim + GH 478 (30 + 10 μg) 0 0 9 Cefazolin (30 μg) GH 478 (10 μg) Cefazolin + GH 478 ( 30 + 10 μg) 0 0 11 Cefoxitin (30 μg) GH 478 (10 μg) Cefoxitin + GH 478 (30 + 10 μg) 11 0 11 Cefotaxime (30 μg) GH 478 (10 μg) Cefotaxime + GH 478 (30 + 10 μg) 0 0 9 Piperacillin (30 μg) GH 478 (10 μg) Piperacillin + GH 478 (30 + 10 μg) 0 11 Oxacillin (30 μg) GH 478 (10 μg) Oxacillin + GH 478 (30 + 10 μg)

0

0

0

Cloxacillin (30 μg)

GH 478 (10 μg) Cloxacillin + GH 478 (30 + 10 μg)

0

0

eleven

Diloxacillin (30 μg)

GH 478 (10 μg) Dicloxacillin + GH 478 (30 + 10 μg)

0

0

0

Ceftriaxon (30 μg)

GH 478 (10 μg) Ceftriaxon + GH 478 (30 + 10 μg)

0

0

0

Moxalactam (30 μg)

GH 478 (10 μg) Moxalactam + GH 478 (30 + 10 μg)

8

0 10

Ceftriaxon (30 μg)

GH 478 (10 μg) Ceftriaxon + GH 478 (30 + 10 μg)

0

0

0

Cefotiam (30 μg)

lmipenem (10 μg) Cefotiam + imipenem (30 + 10 μg)

0

8 fifteen

Piperacillin (30 μg)

Imipenem (10 μg) Piperacillin + imipenem (30 + 10 μg)

0

8 13

Penicillin G (30 μg)

GH 478 (10 μg) Penicillin G + GH 478 (30 + 10 μg)

0

0

14

Meticillin (30 μg)

GH 478 (10 μg) Meticillin + GH 478 (30 + 10 μg)

0

0

0

Cefsudolin (30 μg)

GH 478 (10 μg) Cefsudolin + GH 478 (30 + 10 μg)

0

0

10

 (keep going)

Test strain: Staph. Innsbruck

Inhibition zone diameter (mm)

Vancomycin (30 μg)

twenty

GH 478: (1R.5S.6S) -6 - [(R) -1-hydroxyethyl] -2-methoxymethylthio-1-methylcarbapen-2-em-3-potassium carboxylate

GH 570: (1R.5S.6S) -2 - [(2-Aminoethyl) oxy] methylthio-6 - [(R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic

GH 519: (1R.5S.6S) -2 - [(N-acetylamino) methylthio] -6 - [(R) -1-hydroxyethyl] -1-methylcarbapen-2-em-3- potassium carboxylate

Example 2

Minimum inhibitory concentrations

[0059] The minimum inhibitory concentrations were determined using Difco nutritive agar. Appropriate volumes of 0.1% aqueous solutions of antibiotics were added in sterile dishes (8.5 cm) diluted in half and mixed with 10 ml of sterile liquid agar of 50 ° C. The solid agar was inoculated with 3 μl of a 0.5 McFarland bacterial solution in Difco's nutrient broth, corresponding to approx. 105 forming units of colonies Bacterial growth was recorded after 20 hrs of incubation at 37 ° C.

 Minimum inhibitory concentration (μg / ml) MRSA 7268/02 Staph. Innsbruck

Epicillin 32 32 Amoxicillin 32 64 Meropenem 16 32 Cefoxitin 32

Cefotiam / imipenem 16 +16 Piperacillin / meropenem 8 + 8 16 + 16 Piperacillin / imipenem 16 + 16 16 + 16

Epicillin / meropenem 2 + 2 4 + 4 Epicillin / imipenem 1 + 1 4 + 4

Example 3

In vivo activity

[0060] In vivo activity was determined through a mouse septicemia assay using animals immunocompetent 30 g weight (6 animals per group). The infection was carried out with MRSA München 12797 at a concentration of approx. 2 x 109 cfu / mouse via i.v. (lethal dose). The therapy was carried out with daily doses of 5 + 5 to 75 + 75 mg / kg s route. C. (equivalent amounts at times of 1 hr and 4hr after infection). The animals were observed for 10 days post treatment.

ED90 meropenem> 75 + 75 mg / kg ED90 meropenem / epicillin: 5 + 5 mg / kg

Example 4

Pharmaceutical Products Production

[0061]

Pill (for oral administration)

(4R.5S.6S) -6- (1'R) -hydroxyethyl) -3-methoxymethylthio-4-methyl-7oxo-1-azabicio [3.2.0] hept-2- ene-2-carboxylate potassium 250 mg Epicillin 500 mg Corn starch 6 mg Magnesium stearate 20 mg Sodium hydrogen carbonate 135 mg Dicalcium phosphate 60 mg Lactose 229 mg

[0062] The active constituent is mixed with dicalcium phosphate, lactose and about half of the corn starch and the bulk is screened. It dries in a high vacuum and is again screened through sieves with mesh widths of 1.00 mm (Filter No. 16). The remaining corn starch and magnesium stearate are added and the mixture is pressed into tablets weighing 1200 mg each and having a diameter of approximately 1.27 cm (0.5 inches).

Parenteral Solution

Blister

[0063]

Meropenem 250 mg Epicillin 250 mg Sodium hydrogen carbonate 135 mg Sterilized water (added from a separate vial using a syringe immediately before use) 4 ml

Ophthalmic solution

[0064]

Meropenem 50 mg Epicillin 50 mg Sodium hydrogen carbonate 27 mg Hydroxypropylmethylcellulose 5 mg Sterilized water (a 2 ml separate vial is added using a syringe immediately before use)

Earphone solution

[0065]

Meropenem 50 mg Epicillin 50 mg Sodium hydrogen carbonate 27 mg Benzalkonium chloride 0.1 mg

Sterilized water (added from a separate vial using a syringe immediately before use) 2 ml 5 Topical cream or ointment

[0066]

Meropenem 50 mg Epicillin 50 mg Polyethylene glycol 4000 400 mg Polyethylene glycol 400 1.0 g

[0067] The active component in the above preparations can be mixed alone or together with other biologically active components, for example with antibacterial agents such as vancomycin or linezolide or with other therapeutic agents, such as probenicid.

[0068] It is understood that the specification and examples are illustrative but not restrictive of the present invention and that the other embodiments in the spirit and scope of the invention will themselves suggest to those skilled in the art.

Claims (12)

one.

 Active pharmaceutical composition for Staph. aureus resistant to anti-MRSA and bactericidal methicillin containing a carbapenem and epicillin antibiotic, its salts, prodrug ester or prodrug amide derivatives.

2.

 Composition of claim 1 characterized in that the antibiotic carbapenem has structural formula I

and its pharmaceutically acceptable salts, esters and amide derivatives, wherein R1 denotes hydrogen, hydroxymethyl or 1-hydroxyethyl, R2 denotes hydrogen or methyl and R3 denotes a pharmaceutically acceptable group that is linked to the remaining part of the molecule by a single bond carbon-oxygen or a simple carbon-nitrogen bond and which is selected from the group comprising in substituted or unsubstituted form: alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, N-heterocyclyl, heterocyclyloxy, heterocyclylcarbonyloxy, heterocyclylthiocarbonyloxy, acyloxy, thioacyloxy, alkoxycarbonyloxy , carbamoyloxy, thiocarbamoyloxy, heterocicliloxicarboniloxi, heterocicliloxitiocarboniloxi, Nheterociclicarbamoiloxi, N-heterocicliltiocarbamoiloxi, heterocyclylcarbonylamino, heterocicliltiocarbonilamino, heterocicliloxicarbonilamino, acylamino, alkoxycarbonylamino, alkoxythiocarbonylamino, tioaciclamino, Nheterociclilcarbamoilamino, N-heterocicliltiocarbamoilamino, carbamoylamino, tiocarbam oylamino, imidoylamino, guanidino, N-heterocyclyl-alkoxycarbonylamino, N-heterocyclyl-alkylthiocarbonylamino and N-sulfonylamino where the above-mentioned parts of the molecule alkyl, alkenyl, alkynyl, acyl, thioacyl or imidoyl contain from 1 to 6 carbon atoms and the heterocyclyl group is monocyclic or bicyclic and contains from 3 to 10 ring atoms, from which one or more are selected from the series comprising: oxygen, sulfur and nitrogen and where the substituents of the groups mentioned above R3 can be: alkyl, acyl , thioacyl, heterocyclyl, hydroxyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, amidinoalcoxi, guanidinoalcoxi, acyloxy, heterocyclyloxy, alquilheterocicliloxi, hidroxialquilheterocicliloxi, aminoalquilheterocicliloxi, carbamoyl, alquilocarbamoil, dialquilocarbamoil, carbamoyloxy, alkylcarbamoyloxy, dialkylcarbamoyloxy, thiocarbamoyl, alquiltiocarbamoil, dialquiltiocarbamoil, thiocarbamoyloxy, alquiltiocarbamoiloxi dialkylthiocarb amoiloxi, mercapto, alkylthio, hydroxyalkylthio, aminoalkylthio, monoalquilaminoalquiltio, dialquilaminoalquiltio, amidinoalquiltio, acylthio, heterocyclylthio, alquilheterocicliltio, hidroxialquilheterocicliltio, aminoalquilheterocicliltio, carbamoiltio, monoalquilcarbamoiltio, dialquilcarbamoiltio, tiocarbamoiltio, alquiltiocarbamoiltio, dialquilcarbamoiltio, amino, monoalkylamino, hydroxyalkylamino, aminoalkylamino, dialkylamino, oxo, oximino, or alkylimino, imidoilamino, alquilimidoilamino, dialquilimidoilamino, tetraalkylammonium, cycloalkylamino, heterocyclylamino, alkylheterocyclylamino, heterocyclylcarbonylamino, alquilheterociclilcarbonilamino, acylamino, amidino, monoalquilamidino, dialquilamidino, guanidino, alkylguanidino, -dialkylguanidino, carbamoylamino, tiocarbamoilamino, alquilcarbamoilamino, tiocarbamoilamino, alquiltiocarbamoilamino, nitro, chloro , bromine, fluoro, iodine, cyano azide, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfamoyloxy, alkylsulfamoyloxy, alkyls ilsulfonyloxy or sulfo, sulfoxy, carboxamido, N-monoalkylcarboxamido, N, N-dialkylcarboxamido or carboxy, where the substituents, independently of each other, meet once or several times and its alkyl fraction contains 1 to 6 carbon atoms, and where the heterocyclic fraction is monocyclic or bicyclic and contains 3 to 10 ring atoms, of which one or more are selected from the series comprising: oxygen, sulfur and nitrogen.

3.

 Pharmaceutical composition of claim 1, characterized in that the antibiotic of carbapenem is selected from the group comprising imipenem, meropenem, panipenem, ertapenem, biapenem, doripenem, saftrinem, lenapenem, tebipenem, tomopenem, S-4661, SM 216601, GV 129606; ZD-4433; ER-35786; R83201, R 95867, DU-6681; BO-2502A, BO-3482; DK-35C, DA-1131; S-4661; L-646591; L-786,392; L-695,256; L786,392; L-084; L-036; DZ-2640; CS-834; GV104326; GV-118819, GV 143253; MK-0826; J-110,441; J-111225; FR21818; DX-8739; CS-023; ME-1036, CP 5068, CL 188624; CL-190294; CL191121; OCA-983; T-5575 and PZ-601,

Four.

 Pharmaceutical composition of claim 3, characterized in that the antibiotic of carbapenem is selected from the group comprising imipenem, meropenem, panipenem, ertapenem, biapenem, doripenem, saftrinem, lenapenem, tebipenem and tomopenem.

5.

Pharmaceutical composition of claim 4 characterized in that the carbapenem antibiotic is selected from the group imipenem, meropenem and ertapenem.

6.

 Pharmaceutical composition of any one of claims 1 to 5, comprising effective amounts of a carbapenem and epicillin antibiotic and a pharmaceutically acceptable carrier or diluent.

7.

 Use of a pharmaceutical composition according to any one of claims 1 to 5 to prepare a medicament for treating a methicillin-resistant, suspected or confirmed staph MRSA or MRSE epidermis infection.

8.

 Use of effective amounts of a carbapenem and epicillin antibiotic according to any one of claims 1 to 5 to prepare a medicament for a separate application of both active components in an antibacterial manner to treat a suspected or confirmed MRSA or MRSE infection.

9.

 Process for preparing the composition according to any of claims 1 to 5, which comprises incorporating antibacterial effective amounts of a carbapenem and epicillin antibiotic into a pharmaceutically acceptable carrier or diluent.

10.

 Process for preparing a medicament according to any one of claims 1 to 5 for the separate application of both active components in an antibacterial manner to treat a suspected or confirmed MRSA or MRSE infection, characterized by the fact that antibacterially effective amounts of an antibiotic of carbapenem and epicillin according to any one of claims 1 to 4 are incorporated into a pharmaceutically acceptable carrier or diluent.

eleven.

 In vitro inhibition method of suspected or confirmed MRSA or MRSE, comprising administering effective amounts to said bacteria of a carbapenem and epicillin antibiotic according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or diluent.

12.

 In vitro inhibition method of suspected or confirmed MRSA or MRSE, comprising a separate administration of effective amounts to said bacteria of an antibiotic of carbapenem and epicillin according to any of claims 1 to 5 and a pharmaceutically acceptable carrier or diluent.